1. Field of the Invention
The present invention provides for synthetic processes for the making of substituted 3-((pyrrol-2-yl)methylene)-2-pyrrolones, including sunitinib.
2. Description of the Related Art
3-((Pyrrol-2-yl)methylene)-2-pyrrolones (3; FIG. 1) occur as core structural units in a significant number of reported chemical structures1, many of which have been synthesised for biological testing for their potential use as drugs. Typically the 2-pyrrolone sub-unit manifests itself as a substituted or unsubstituted 2-indolinone (i.e., 3-((pyrrol-2-yl)methylene)-2-indolinones 3b), or as a 2-pyrrolone fused with a heterocyclic aromatic ring. For convenience we will class 3-((pyrrol-2-yl)methylene)-2-indolinones 3b as 3-((pyrrol-2-yl)methylene)-2-pyrrolones 3. The methylene group that bridges the pyrrolone and pyrrole rings can be partially substituted (i.e., R5═H) or fully substituted (e.g., R5=alkyl, aryl, COR). As such, the 3-((pyrrol-2-yl)methylene-2-pyrrolone moiety can be found in biologically active compounds being investigated for the treatment of, or have been suggested to have the potential for treating, a range of diseases including cancer,2 inflammation, a range of autoimmune diseases (including rheumatoid arthritis and multiple sclerosis3), Parkinson's disease,4 and cardiovascular disease. Examination of the literature revealed that the 3-((pyrrol-2-yl)methylene)-2-pyrrolone moiety seen in biologically active compounds modulates the activity of protein kinases. Protein kinases are critical regulators of cellular processes in normal tissues and in diseased tissue, including cancer. Thus, the efficient synthesis of this structural moiety is of significant relevance to the identification, development and manufacture of new drugs to treat disease. 1As confirmed using a SciFinder search on this molecular moiety (24 Apr. 2010).2Bioorganic & Medicinal Chemistry Letters, 2002, 12, 2153-2157.3WO2005058309A1; Medicinal Chemistry, 2005, 48, 5412-5414.4WO2009030270A1.
One particular example of a clinically useful 3-((pyrrol-2-yl)methylene)-2-pyrrolone is N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-yliden)methyl]2,4-dimethyl-1H-pyrrole-3-carboxamide) (C22H27FN4O2; MW 398.47 g/mol), otherwise known as sunitinib (1) which is used as its L-malic acid ((2S)-hydroxy-butanedioic acid) salt 25 as the active pharmaceutical ingredient in SUTENT® (FIG. 2). SUTENT®, previously known as SU11248, is marketed by Pfizer Inc. The active ingredient is a first-in-class orally available, small molecule receptor tyrosine kinase (RTK) inhibitor which is used for the treatment of gastrointestinal stromal tumor (GIST) and renal cell carcinoma (RCC). Sunitinib and/or its salt is/are also being evaluated in a broad range of solid tumors, including breast, lung, thyroid and colorectal cancers. 5C26H33FN4O7, and a MW of 532.6 (g/mol).
Other biologically active compounds of interest that possess the 3-((pyrrol-2-yl)methylene)-2-pyrrolone moiety include those shown in FIG. 3. Compounds such as SU5416 and SU6597 have been studied for the possible use in the inhibition of the proliferation of tumors (“such as SCLC, gastrointestinal stromal tumors, seminomas, and leukemias.”6) and SU6577 for a “therapy targeting a cause of mastocytosis”7, and PHA665752 for antitumor activity, and A-432411 as a microtubule inhibitor, and BX-5178 for cancer. 6Cancer Research 2001, 61, 3660-3668.7Journal of Investigative Dermatology 2000, 114, 392-394.8Bioorganic & Medicinal Chemistry Letters, 2002, 12, 2153-2157.
3-((Aryl)methylene)-2-pyrrolones such as SU4984 might also be useful for disease therapies, and these analogues of 3-((pyrrol-2-yl)methylene)-2-pyrrolones might be applicable to synthesis using the processes described in this invention.